How Depression Shrinks the Brain

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Certain brain regions in people with major depression are smaller
and less dense than those of their healthy counterparts. Now,
researchers have traced the genetic reasons for this shrinkage.

A series of genes linked to the function of synapses, or the gaps
between brain cells crucial for cell-to-cell communication, can
be controlled by a single genetic "switch" that appears to be
overproduced in the brains
of people with depression, a new study finds.

"We show that circuits normally involved in emotion, as well as
cognition, are disrupted when this single transcription factor is
activated," study researcher Ronald Duman, a professor of
psychiatry at Yale University, said in a statement.

Transcription factors are proteins that help control which
genetic instructions from DNA will be copied, or transcribed, as
part of the process of building the body's proteins.

Shrinking brain

Brain-imaging studies,
post-mortem examinations of human brains and animal studies
have all found that in depression, a part of the brain called the
dorsolateral prefrontal cortex shrinks. The neurons in this
region, which is responsible for complex tasks from memory and
sensory integration to the planning of actions, are also smaller
and less dense in depressed people compared with healthy people.
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Duman and his colleagues suspected that these neuronal
abnormalities would include problems with the synapses, the
points where brain cells "talk" to one another. At synapses,
neurons release neurotransmitters that are picked up by their
neighbors, carrying signals from cell to cell at rapid speed.

The researchers conducted gene profiling on the postmortem brain
tissue of both depressed and mentally healthy subjects. They
found a range of genes that were significantly less active in
depressed people's dorsolateral prefrontal cortexes, particularly
five related to synaptic function: synapsin 1, Rab3A, calmodulin
2, Rab4B and TUBB4.

Synaptic damage

These genes are all involved in either the chemical signaling
that occurs at synapses or the cellular recycling and
regeneration processes that keep the synapse-system humming.
All five are regulated by a single transcription factor
called GATA1, which was overproduced in
depressed brains.

The researchers activated GATA1 in the brains of rats and found
that the factor decreased the complexity of the long, branchlike
projections, or dendrites, of brain cells. These projections are
the telephone lines that carry synaptic messages, integrating all
the information a cell receives.

Extra GATA1 also increased depression-like behavior in the rats.
For example, when given a swimming task, rats with extra GATA1
stayed immobile in the water longer, a signal of despair, than
normal-GATA1 rats, the researchers report today (Aug. 12) in the
journal Nature Medicine.

The researchers believe the damage could be a result of chronic
stress, and they hope the findings lead to new depression
treatments.

"We hope that by enhancing synaptic connections, either with
novel medications or behavioral therapy, we can develop more
effective antidepressant therapies," Duman said.